ASH 2023 preview – small-molecule duels

With biologicals taking something of a back seat, this year’s ASH could see an increased focus on duels featuring small-molecule approaches. Among these one of the most closely watched is Menin inhibition, where the current battle between Kura and Syndax is seeing a challenge from Johnson & Johnson’s JNJ-75276617.

However, based on the ASH abstract at least, Kura and Syndax might be breathing sighs of relief. In BTK inhibition the established players Imbruvica and Brukinsa will face further challenges from Jaypirca and a new project described as being covalent and non-covalent, while several BCR-ABL inhibitors are seeking a place in CML that’s resistant to current tyrosine kinase drugs.

For Menin inhibitors the battleground is AML, with Syndax’s revumenib showing potential in NPM1m as well as KMT2Ar disease, and Kura’s ziftomenib only in the former genetic subtype. Each also has a different toxicity profile, with the focus being QTc prolongation for Syndax and differentiation syndrome for Kura.

The two companies’ ASH updates don’t change the narrative, but what’s new is J&J’s JNJ-75276617 showing a CR rate of just 20% at high doses – inferior to both on a cross-trial basis. JNJ-75276617 is, however, active in both genetic subtypes, raising further questions about ziftomenib’s lack of efficacy in patients with KMT2A-rearranged AML, where Kura has discontinued work.

Syndax yesterday closed up 6%, though some of this will have been down to ASH selecting the Agave-201 trial of its Incyte-partnered anti-CSF-1R MAb axatilimab in graft-versus-host disease for presentation at a plenary session. All the ASH abstracts went live yesterday except for late-breakers, which will be unveiled on 21 November; for many the most up-to-date results will only come at ASH itself.

T-cell lymphoma

A separate battle will take place in peripheral T-cell lymphoma, where rival EZH1/2 inhibitors from Daiichi Sankyo and Haihe Biopharma will be joined by golidocitinib, a Jak1 inhibitor being developed by China’s Dizal.

Meanwhile, the established players in BTK inhibition are facing a challenge from non-covalent molecules, said to be able to overcome the C481 mutation, the most advanced of which is Lilly’s Jaypirca. However, Jaypirca is so far approved only in mantle cell lymphoma, and not in Imbruvica and Brukinsa’s major CLL setting.

ASH will see the CLL cohort of Jaypirca’s Bruin study, a dataset now under review by the FDA. An intriguing presentation will come from Newave, a Lupeng Pharmaceutical subsidiary, in CLL patients who have failed covalent BTK inhibition and received LP-168, a BTK inhibitor said to bind covalently as well as non-covalently; still, the data come up short of Jaypirca’s.

Selected oral ASH presentations on small molecules

Note: excludes posters and late-breaking abstracts.

The ASH press programme, from which only non-late-breakers are disclosed at present, will highlight the phase 3 Transform-1 trial of AbbVie’s BCL-2 inhibitor navitoclax in front-line myelofibrosis, where a Jakafi combo has beaten Jakafi alone in terms of 35% spleen volume reduction (p<0.0001).

BeiGene’s rival BCL-2 inhibitor sonrotoclax recently entered phase 3 for first-line and post-BTK CLL, but ASH will see it in the unusual setting of multiple myeloma. The meeting will also see myelofibrosis data from three rival BET inhibitors, Bristol’s BMS-986158, MorphoSys’s pelabresib and Incyte’s INCB057643.

Finally, the CML space, where Novartis’s Gleevec is a first-line standard, has already seen the Swiss firm launch Scemblix for patients who progress on Gleevec or other tyrosine kinase inhibitors. Rival BCR/ABL inhibitors are in development, two of which, Ascentage’s olverembatinib and Shenzhen TargetRx’s TGRX-678, will feature at ASH presentations in TKI-resistant CML.

Major molecular response in the former’s registrational dataset looks similar to Scemblix’s 25%, though to what extent the two CML populations are comparable isn’t clear. TGRX-678 has yielded a 19% rate, though the CML patients in its study seem to be more refractory, having in some cases failed Scemblix or – intriguingly – olverembatinib.

The ASH conference takes place in San Diego on 9-12 December.